Table 1.
Overview of the summary results statistics used in the Mendelian randomization analysis
| Phenotype | Data source | Study design | Population | Sample size | Phenotype definition | Inclusion/Exclusion criteria | Number of genetic variants | Genetic variant selection | Genetic Variants extracted | |
|---|---|---|---|---|---|---|---|---|---|---|
| 1. BMI | ||||||||||
| BMI [48, 49] | Exposure | UK Biobank and GIANT Consortium | Continous trait | European individuals | 434,794 | Phenotypes were rank inverse normalized transformed and residualized. | None stated | 469 | P < 10−8 | Additional file 1: Table S1. |
| 2. Ovulatory function | ||||||||||
| Years ovulating* | Exposure | Own GWAS in UKBB | Continous trait | European women | 118,227 | Years ovulating = years menstruating - years on pill - 0.75 * (live births + stillbirths) | Women with a history of hysterectomy before menopause (N = 12,539), who were not sure of their age at menopause due to their hysterectomy (N = 30,788), or early menopause (< 40 years; N = 3144) were excluded from the analysis. | 11 | p<5x10-8 | Additional file 1: Table S2. |
| Age at Menarche [50, 51] | Exposure | ReproGen Consortium | Continous trait | European women | 182,416 | Self-reported age at menarche | Women who reported their age at menarche as <9 years or >17 years were excluded from the analysis. | 110 | p<5x10-8 | Additional file 1: Table S3. |
| Age at Menopause [52, 53] | Exposure | ReproGen Consortium | Continous trait | European women | 69,360 | self-reported and defined as the age at last naturally occurring menstrual period followed by at least 12 consecutive months of amenorrhea. | Included women who were 40–60 years of age, excluding women with menopause induced by hysterectomy, bilateral ovariectomy, radiation or chemotherapy and those using hormone replacement therapy before menopause. | 41 | p<5x10-8 | Additional file 1: Table S4. |
| 3. Reproductive function | ||||||||||
| Number of live births* [54, 55] | Exposure | Own GWAS in UKBB | Continous trait | European women | 237,768 women reporting how many children they mothered, 199,570 men reporting how many children they had fathered and 430,466 individuals reporting how many siblings they have. | Number of children mothered adjusted for paternal and child effect. | Participants reporting greater than 10 siblings (N = 1,720, 0.4%) or children (mothered N = 18, 0.007%; fathered N = 43, 0.02%) were recoded to have 10. | 6 | p<5x10-8 | Additional file 1: Table S5. |
| Age at last live birth* | Exposure | Own GWAS in UKBB | Continous trait | European women | 220,419 | Age at last live birth was defined as the age of primiparous women at birth (for women who reported only one live birth) or the age at last live birth as reported by women who reported multiple live births. | Women with inconsistent reports of age at last live birth across the four data collection instances were excluded (n = 263). | 19 | p<5x10-8 | Additional file 1: Table S6. |
| 4. Oral contraceptive pill | ||||||||||
| We did not identify any genome-wide significant (p<5x10-8) SNPs associated with years taking the oral contraceptive pill, and this phenotype was therefore not taken forward in MR analyses. | ||||||||||
| Outcome | ||||||||||
| Endometrial Cancer [31] | Outcome | ECAC and E2C2 Consortium | Case/Control | European women | 12,270 cases and 46,126 controlsa | Meta-analysis from cohorts using different case inclusion criteria | None stated | (10 as exposure in bidirectional MR) | Additional file 1: Table S7. | |
| (Exposure in bidirectional MR) | ||||||||||
*Exposures considered primary exposures for the univariate Mendelian randomization analysis [31, 48–55]
aExcluding UK Biobank. GWAS, genome-wide association study; BMI, body mass index; MR, Mendelian randomization; ECAC, Endometrial Cancer Association Consortium; E2C2, Epidemiology of Endometrial Cancer Consortium